- Email: [email protected]
The use of typical and atypical neuroleptics for controlling behavioral disturbances in dementia: A retrospective study
S324
P4. Degenemtive and neurological disorders
These tindings are intriguing in light of the reported muscarinic antagonism with olanzapine.
[p.4.018/
in vitro
Glutamate levels in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. A reappraisal using a new HPLC method with coulometric detection in a large cohort of patients
0. Spreux-Varoquaux, L. Lacomblez, G. Bensimon, E Salachas, M. Dib, A. Marouan, P. Julien, PE Pradat, N. LeForestier, V Meininger. University Paris V and VT, Pharmacology, Versailles Hospital; Neurology and Pharmacology, H6pital Piti&Salp&ri&, Paris, France Glutamate is one of several potential pathogenic factors involved in the biological mechanisms underlying arnyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease involving motor neurons. However, the etiology of this disease is widely believed to be heterogeneous, leading to the possibility that patient subgroups with different pathophysiology may exist. The concentration of glutamate in cerebrospinal fluid (CSF) was measured using a new HPLC method with coulomenic detection in a total of 483 patients, 377 ALS patients, 88 neurological patients and 18 normal controls. This is the largest cohort ever obtained for such a study. In ALS patients, and only in these subjects, the existence of two groups was observed, one with concentrations of glutamate in the control range, and one with high glutamate concentrations. High concentrations of glutamate in CSF were correlated with more impaired limb function and with a higher speed of muscle deterioration; no difference in survival time was observed between the two groups. These results suggest that elevations of CSF glutamate concentrations could reflect the intensity of cell insult in the spinal cord. It remains to be determined if the group of patients with high CSF glutamate concentrations represents a specific subgroup of patients in terms of mechanism of disease, or only in terms of the spatial extent of motor neuron insult.
IP.4.019]
Role of CYPZDI in the metabolism and elimination of the parkinsonism inducing compound 1,2,3,4,-tetrahydroisoquinoline in the rat
E. Lorenc-Koci, J. Wojcikowski, M. Kot, W.A. Daniel. Institute Pharmacology Polish Academy of Sciences, Krakbw, Poland 1,2,3,4-Tetrahydroisoquinoline (TIQ) and its derivatives, being structurally related to the selective dopaminergic toxin l-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), are proposed as putative endogenous toxins that may be involved in the etiology of Parkinson’s disease. These substances are widely spread in the environment, being present in many plants and foods, and they readily cross the blood-brain barrier. They occur naturally in mammalian brains where they can be formed by condensation of biogenic amines with aldehydes. Recently utmost attention has been focused on cytochrome P450 2D6 (CYP2D6) enzymes as susceptibility factors in PD. It has been postulated that a defect in CYP2D6 functioning may be related to an early onset of the desease. CYP2D6 in humans corresponds to CYP2Dl in rats. TIQ is metabolized by CYP2Dl to 4-hydroxytetrahydroisoquinoline (COH-TIQ) in rat liver. It has been hypothesized that a lack of or a
decreased activity of CYP2D6/CYP2Dl may lead to accumulation of TIQ in the brain. The aim of our study was to examine the effect of CYP2Dl inhibition on the concentration of TIQ and its main metabolite 4-OH-TIQ in blood plasma and the brain. TIQ was administered alone or in a combination with quinine, a specific inhibitor of CYPZDl. Thirty minutes after administration of quinine in doses of 20 and 50 mg/kg i.p., rats were given TIQ (40 mg/kg i.p.). Two hours after TIQ injection, the animals were killed, their brains were excised and blood samples were collected. Additionally, rats treated with 100 mgikg of TIQ were killed at 2, 12 and 24 h after its injection. Concentrations of TIQ and 4-OH-TIQ were assayed by an HPLC method with UV detection. Our results showed that, irrespective of the TIQ dose used (40, 100 mg/kg), the brain level of this compound was c.a. 8 times higher than its content in blood plasma. After a longer time interval (12 h) TIQ concentrations decreased rapidly both in the plasma and brain, furthermore 24 h after administration only its trace amounts could be detected in both those tissues. The concentration of 4-OH-TIQ was very low in both blood plasma and the brain compared to that of TIQ in either tissue. However, the brain concentration of 4-OH-TIQ was 2-3 times higher than that in blood plasma. Administration of TIQ (40 mg/kg) jointly with quinine (20 and 50 mg/kg) had no effect on TIQ concentration in blood plasma and the brain; however, quinine decreased the level of 4-OH-TIQ in either tissue. Our results show that inhibition of CYPZDI has no effect on the brain level of TIQ. Thus the postulated role of CYP2D6 defect in the etiology of Parkinson’s disease does not seem to be connected with inhibition of TIQ elimination from the organism which would lead to an increase in TIQ concentration in the brain.
Ip.4.020]
The use of typical and atypical neuroleptics for controlllng behavioral disturbances in dementia: A retrospective study
J. Ballesteros, M. Martin, M. Lopez de Argumedo, C. Garcia, F.J. Blanco, J. De Blas, G. Baraibar, L. Minguez, J.A. Agtiero. Institute of Psychiatric Research, Bilbao, Spain Based on several reviews (Schneider et al, 1990; Lanctot et al, 1998), neuroleptics are frequently used as off-label medication for controlling the behavioral disturbances (BD) which are common in the last stages of dementia (DeIIlippi & Crismon, 2000). Nevertheless very little is known on the comparative effectiveness of typical and atypical neuroleptics. The objective of this paper is to present preliminary data regarding typical (haloperidol, thioridazine) and atypical neuroleptics (olanzapine, risperidone) for controlling BD in dementias. The study is retrospective and is based on the analysis of the clinical charts of 102 patients (37 males/65 females) with dementia who were treated with neuroleptics (16 olanzapine/20 haloperidol/30 thioridazine/36 risperidone) because BD for a maximum period of three months. The outcome variables were: the improvement of BD over the three months period as rated by their clinicians, the Clinical Global Impression (CGI), and the time on treatment (weeks) until BD resolution. There were not differences between study arms regarding the improvement of BD (Fisher’s exact test P = 0.60), the CGI (F-test (3, 96) = 1.3 1; P = 0.28) or the time-on-treatment (generalized Wilcoxon test = 4.54; 3 df; P = 0.21). The unique difference between arms appeared in the survival analysis when the sample
RX Degenemtive and neurological disorders was stratified by cognitive impairment, showing that less impaired individuals improve faster in the haloperidol arm (generalized Wilcoxon test = 8.41; 3 df; P = 0.04). Nevertheless this group also showed more extrapyramidal signs. Randomized clinical trials including not only placebo and any active drug but several treatment arms are needed before recommending guidelines on the treatments by neuroleptics of BD in dementia. This study was supported by a research grant from Lilly (Spain)
S325
catabolism. Inhibitory effect on N-oxidation catabolic pathway of dopamine may protect the dopamine neurons against oxidative damage. Moreover the increase in MHPG concentration which follows 1MTIQ administration provides further evidence that noradrenaline neurons are involved in the 1MTIQ mechanism of action. Demonstration of biochemical effects produced by 1MTIQ in mice and rats on neurotransmitters utilization permits better understanding of general mechanisms which may be related to neuroprotection of these endogenous compound. References
[l] Defilippi JL, Crismon ML. Phannacotherapy 2ooO; 20: 23-33 [2] Lanctdt KL et al. J Clin Psychiatry 1998; 59: F&561 [3] Schneider LS et al. J Am Geriatr Sot 1990; 38: 553-563
IP.4.0211 The effect of single I-methyl-1,2,3,4tetrahydroisoquinoline (1MTlQ) administration on concentration of noradrenaline and dopamine in the mouse and rat brain L. Antkiewicz-Michaluk, B. Karolewicz’, I. Roman&a, J. Vetulani. Institute of Pharmacoloav, Polish Academy of Sciences, Kratiw. Poland Derivatives of tetrahydroisoquinolines (TIQs) are present in the brain, some are endogenous, may also pass through the bloodbrain barrier and accumulate in the brain after food ingestion. Many of them are of physiological importance and have aroused a considerable interest as molecular species that may be implicated in etiology of Parkinson’s disease (Antkiewicz-Michaluk et al., 1997, 2000). Recent studies have reported that l-methyl-l ,2,3,4tetrahydroisoquinoline (IMTIQ) exhibits potential neuroprotective properties. The aim of present studies was to investigate the effect of single 1MTIQ administration on concentration of dopamine (DA) and its metabolites: 3,4&hydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-metoxytyramine (3MT) and the level of noradrenaline (NA) and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG). Studies were performed by use of high performance liquid chromatography (HPLC) with electrochemical detection. 1MTIQ was injected to mice in doses 25 and 50 mg/kg and to rats in dose 100 mg/kg (ip.). Experiments were carried out 2 or 3 hours after injection in the whole brain (minus cerebellum) of Swiss Albino mice and in the striatum of Wistar rats. The rate of dopamine catabolism in the rat striatum along the N-oxidative and 0-methylation pathways was assessed by calculation of the ratio of appropriate metabolites to dopamine concentration. IMTIQ did not change the rate of total dopamine catabolism, it strongly inhibited the oxidative MAOdependent N-oxidation and significantly activated the COMT dependent 0-methylation. The level of intemeuronal metabolite, DOPAC was strongly depressed (by 60%) while the level of extraneuronal metabolite, 3MT, was significantly elevated (by 160%). One of the major noradrenaline metabolite MHPG was examined in mice brain, where is only found in the unconjugated form and represent the major cerebral transformation of noradrenaline. We have found that 1MTIQ produces partially yohimbine-like effect on noradrenaline metabolism in the mouse brain. Two hours after 1MTIQ injection we have observed marked increase in the level of noradrenaline metabolite MHPG (by X-60%) without changes in NA concentration. In the present study we demonstrated for the first time that 1MTIQ may change the pathways of DA
[I] Antkiewicz-Michaluk, L., Szczudlik, A., Rrygowska-Wajs, A., Romanska, I., Vetulani, J., 1997. Increase in salsolinol level in the cerebrospinal fluid of parkinsonian patients is related to dementia: advantage of a new high-performance liquid chromatography methodology. Biol. Psych. 42, 514-518. [2] Antkiewicz-Michaluk, L., Michaluk, J., Roman&a, I., Papla, I., Vetulam, J., 2000. Antidopaminergic effects of 1,2,3,4-tetrahydroisoquinoline and salsolinol. J. Neural. Transm. 107, 1009-1019.
lp.4.0221
Significant improvements in symptoms in patients with ‘advanced moderate’ AD during galantamine treatment
A. Kurz’ S. Schwalen*. ‘Technische Universitiit M&hen, Munich; ‘Janssen-Cilag GmbH, Neuss, Germany Objectives: Galantamine is a cholinergic agent with a dual mode of action that has consistently shown a broad spectrum of efficacy in patients mild-to-moderate Alzheimer’s disease (AD) during pivotal controlled clinical studies. In order to evaluate the potential benefits of this novel agent in patients with more severe AD, we assessed the efficacy of gala&mine in a post-hoc analysis of patients identified as having ‘advanced moderate’ AD in pooled data from four large-scale, placebo-controlled Phase III trials. Methods: A total of 245 patients with Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) scores > 30 and 63 patients with baseline Mini-Mental State Evaluation (MMSE) scores < 12 were classed as having ‘advanced moderate’ AD. Patients from both subgroups were assessed for responses of cognitive and functional abilities, behavioural alterations and changes in global impression to treatment with galantamine 24 mg/day during pivotal clinical studies compared with respective placebo subgroups (n = 257 and n = 61, respectively). Results: After 5-6 months of treatment with galantamine 24 mgday, patients with ‘advanced moderate’ AD showed significantly improved cognitive abilities compared with placebo in the joint data-set pooled from pivotal clinical trials @ < 0.001). In the subgroup of patients with baseline ADAS-cog > 30, patients improved by 2.8 points on the ADAS-cog, compared with a 3.6point decline with placebo (treatment difference, p < 0.001). Approximately half (46%) of these patients improved by 24 points on the ADAS-cog with galantamine compared with 16% with placebo @ < O.OOl), and the mean improvement in the upper quartile (top 25%) of ADAS-cog changes from baseline was 10.6 points compared with 4.8 points in placebo-treated patients. A further 25% showed improvements of 5.1 points compared with a decline of approximately 1.9 points with placebo. In patients who joined the studies with baseline MMSE < 12, ADAS-cog scores improved by 0.9 points in galantamine-treated patients compared with a 5.8-point decline in patients who received placebo (treatment difference, p < 0.001); 26.8% of these galantamine-treated patients improved by 24 points on ADAS-cog compared with
P4. Degenemtive and neurological disorders
These tindings are intriguing in light of the reported muscarinic antagonism with olanzapine.
[p.4.018/
in vitro
Glutamate levels in cerebrospinal fluid of patients with amyotrophic lateral sclerosis. A reappraisal using a new HPLC method with coulometric detection in a large cohort of patients
0. Spreux-Varoquaux, L. Lacomblez, G. Bensimon, E Salachas, M. Dib, A. Marouan, P. Julien, PE Pradat, N. LeForestier, V Meininger. University Paris V and VT, Pharmacology, Versailles Hospital; Neurology and Pharmacology, H6pital Piti&Salp&ri&, Paris, France Glutamate is one of several potential pathogenic factors involved in the biological mechanisms underlying arnyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease involving motor neurons. However, the etiology of this disease is widely believed to be heterogeneous, leading to the possibility that patient subgroups with different pathophysiology may exist. The concentration of glutamate in cerebrospinal fluid (CSF) was measured using a new HPLC method with coulomenic detection in a total of 483 patients, 377 ALS patients, 88 neurological patients and 18 normal controls. This is the largest cohort ever obtained for such a study. In ALS patients, and only in these subjects, the existence of two groups was observed, one with concentrations of glutamate in the control range, and one with high glutamate concentrations. High concentrations of glutamate in CSF were correlated with more impaired limb function and with a higher speed of muscle deterioration; no difference in survival time was observed between the two groups. These results suggest that elevations of CSF glutamate concentrations could reflect the intensity of cell insult in the spinal cord. It remains to be determined if the group of patients with high CSF glutamate concentrations represents a specific subgroup of patients in terms of mechanism of disease, or only in terms of the spatial extent of motor neuron insult.
IP.4.019]
Role of CYPZDI in the metabolism and elimination of the parkinsonism inducing compound 1,2,3,4,-tetrahydroisoquinoline in the rat
E. Lorenc-Koci, J. Wojcikowski, M. Kot, W.A. Daniel. Institute Pharmacology Polish Academy of Sciences, Krakbw, Poland 1,2,3,4-Tetrahydroisoquinoline (TIQ) and its derivatives, being structurally related to the selective dopaminergic toxin l-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), are proposed as putative endogenous toxins that may be involved in the etiology of Parkinson’s disease. These substances are widely spread in the environment, being present in many plants and foods, and they readily cross the blood-brain barrier. They occur naturally in mammalian brains where they can be formed by condensation of biogenic amines with aldehydes. Recently utmost attention has been focused on cytochrome P450 2D6 (CYP2D6) enzymes as susceptibility factors in PD. It has been postulated that a defect in CYP2D6 functioning may be related to an early onset of the desease. CYP2D6 in humans corresponds to CYP2Dl in rats. TIQ is metabolized by CYP2Dl to 4-hydroxytetrahydroisoquinoline (COH-TIQ) in rat liver. It has been hypothesized that a lack of or a
decreased activity of CYP2D6/CYP2Dl may lead to accumulation of TIQ in the brain. The aim of our study was to examine the effect of CYP2Dl inhibition on the concentration of TIQ and its main metabolite 4-OH-TIQ in blood plasma and the brain. TIQ was administered alone or in a combination with quinine, a specific inhibitor of CYPZDl. Thirty minutes after administration of quinine in doses of 20 and 50 mg/kg i.p., rats were given TIQ (40 mg/kg i.p.). Two hours after TIQ injection, the animals were killed, their brains were excised and blood samples were collected. Additionally, rats treated with 100 mgikg of TIQ were killed at 2, 12 and 24 h after its injection. Concentrations of TIQ and 4-OH-TIQ were assayed by an HPLC method with UV detection. Our results showed that, irrespective of the TIQ dose used (40, 100 mg/kg), the brain level of this compound was c.a. 8 times higher than its content in blood plasma. After a longer time interval (12 h) TIQ concentrations decreased rapidly both in the plasma and brain, furthermore 24 h after administration only its trace amounts could be detected in both those tissues. The concentration of 4-OH-TIQ was very low in both blood plasma and the brain compared to that of TIQ in either tissue. However, the brain concentration of 4-OH-TIQ was 2-3 times higher than that in blood plasma. Administration of TIQ (40 mg/kg) jointly with quinine (20 and 50 mg/kg) had no effect on TIQ concentration in blood plasma and the brain; however, quinine decreased the level of 4-OH-TIQ in either tissue. Our results show that inhibition of CYPZDI has no effect on the brain level of TIQ. Thus the postulated role of CYP2D6 defect in the etiology of Parkinson’s disease does not seem to be connected with inhibition of TIQ elimination from the organism which would lead to an increase in TIQ concentration in the brain.
Ip.4.020]
The use of typical and atypical neuroleptics for controlllng behavioral disturbances in dementia: A retrospective study
J. Ballesteros, M. Martin, M. Lopez de Argumedo, C. Garcia, F.J. Blanco, J. De Blas, G. Baraibar, L. Minguez, J.A. Agtiero. Institute of Psychiatric Research, Bilbao, Spain Based on several reviews (Schneider et al, 1990; Lanctot et al, 1998), neuroleptics are frequently used as off-label medication for controlling the behavioral disturbances (BD) which are common in the last stages of dementia (DeIIlippi & Crismon, 2000). Nevertheless very little is known on the comparative effectiveness of typical and atypical neuroleptics. The objective of this paper is to present preliminary data regarding typical (haloperidol, thioridazine) and atypical neuroleptics (olanzapine, risperidone) for controlling BD in dementias. The study is retrospective and is based on the analysis of the clinical charts of 102 patients (37 males/65 females) with dementia who were treated with neuroleptics (16 olanzapine/20 haloperidol/30 thioridazine/36 risperidone) because BD for a maximum period of three months. The outcome variables were: the improvement of BD over the three months period as rated by their clinicians, the Clinical Global Impression (CGI), and the time on treatment (weeks) until BD resolution. There were not differences between study arms regarding the improvement of BD (Fisher’s exact test P = 0.60), the CGI (F-test (3, 96) = 1.3 1; P = 0.28) or the time-on-treatment (generalized Wilcoxon test = 4.54; 3 df; P = 0.21). The unique difference between arms appeared in the survival analysis when the sample
RX Degenemtive and neurological disorders was stratified by cognitive impairment, showing that less impaired individuals improve faster in the haloperidol arm (generalized Wilcoxon test = 8.41; 3 df; P = 0.04). Nevertheless this group also showed more extrapyramidal signs. Randomized clinical trials including not only placebo and any active drug but several treatment arms are needed before recommending guidelines on the treatments by neuroleptics of BD in dementia. This study was supported by a research grant from Lilly (Spain)
S325
catabolism. Inhibitory effect on N-oxidation catabolic pathway of dopamine may protect the dopamine neurons against oxidative damage. Moreover the increase in MHPG concentration which follows 1MTIQ administration provides further evidence that noradrenaline neurons are involved in the 1MTIQ mechanism of action. Demonstration of biochemical effects produced by 1MTIQ in mice and rats on neurotransmitters utilization permits better understanding of general mechanisms which may be related to neuroprotection of these endogenous compound. References
[l] Defilippi JL, Crismon ML. Phannacotherapy 2ooO; 20: 23-33 [2] Lanctdt KL et al. J Clin Psychiatry 1998; 59: F&561 [3] Schneider LS et al. J Am Geriatr Sot 1990; 38: 553-563
IP.4.0211 The effect of single I-methyl-1,2,3,4tetrahydroisoquinoline (1MTlQ) administration on concentration of noradrenaline and dopamine in the mouse and rat brain L. Antkiewicz-Michaluk, B. Karolewicz’, I. Roman&a, J. Vetulani. Institute of Pharmacoloav, Polish Academy of Sciences, Kratiw. Poland Derivatives of tetrahydroisoquinolines (TIQs) are present in the brain, some are endogenous, may also pass through the bloodbrain barrier and accumulate in the brain after food ingestion. Many of them are of physiological importance and have aroused a considerable interest as molecular species that may be implicated in etiology of Parkinson’s disease (Antkiewicz-Michaluk et al., 1997, 2000). Recent studies have reported that l-methyl-l ,2,3,4tetrahydroisoquinoline (IMTIQ) exhibits potential neuroprotective properties. The aim of present studies was to investigate the effect of single 1MTIQ administration on concentration of dopamine (DA) and its metabolites: 3,4&hydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 3-metoxytyramine (3MT) and the level of noradrenaline (NA) and its metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG). Studies were performed by use of high performance liquid chromatography (HPLC) with electrochemical detection. 1MTIQ was injected to mice in doses 25 and 50 mg/kg and to rats in dose 100 mg/kg (ip.). Experiments were carried out 2 or 3 hours after injection in the whole brain (minus cerebellum) of Swiss Albino mice and in the striatum of Wistar rats. The rate of dopamine catabolism in the rat striatum along the N-oxidative and 0-methylation pathways was assessed by calculation of the ratio of appropriate metabolites to dopamine concentration. IMTIQ did not change the rate of total dopamine catabolism, it strongly inhibited the oxidative MAOdependent N-oxidation and significantly activated the COMT dependent 0-methylation. The level of intemeuronal metabolite, DOPAC was strongly depressed (by 60%) while the level of extraneuronal metabolite, 3MT, was significantly elevated (by 160%). One of the major noradrenaline metabolite MHPG was examined in mice brain, where is only found in the unconjugated form and represent the major cerebral transformation of noradrenaline. We have found that 1MTIQ produces partially yohimbine-like effect on noradrenaline metabolism in the mouse brain. Two hours after 1MTIQ injection we have observed marked increase in the level of noradrenaline metabolite MHPG (by X-60%) without changes in NA concentration. In the present study we demonstrated for the first time that 1MTIQ may change the pathways of DA
[I] Antkiewicz-Michaluk, L., Szczudlik, A., Rrygowska-Wajs, A., Romanska, I., Vetulani, J., 1997. Increase in salsolinol level in the cerebrospinal fluid of parkinsonian patients is related to dementia: advantage of a new high-performance liquid chromatography methodology. Biol. Psych. 42, 514-518. [2] Antkiewicz-Michaluk, L., Michaluk, J., Roman&a, I., Papla, I., Vetulam, J., 2000. Antidopaminergic effects of 1,2,3,4-tetrahydroisoquinoline and salsolinol. J. Neural. Transm. 107, 1009-1019.
lp.4.0221
Significant improvements in symptoms in patients with ‘advanced moderate’ AD during galantamine treatment
A. Kurz’ S. Schwalen*. ‘Technische Universitiit M&hen, Munich; ‘Janssen-Cilag GmbH, Neuss, Germany Objectives: Galantamine is a cholinergic agent with a dual mode of action that has consistently shown a broad spectrum of efficacy in patients mild-to-moderate Alzheimer’s disease (AD) during pivotal controlled clinical studies. In order to evaluate the potential benefits of this novel agent in patients with more severe AD, we assessed the efficacy of gala&mine in a post-hoc analysis of patients identified as having ‘advanced moderate’ AD in pooled data from four large-scale, placebo-controlled Phase III trials. Methods: A total of 245 patients with Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) scores > 30 and 63 patients with baseline Mini-Mental State Evaluation (MMSE) scores < 12 were classed as having ‘advanced moderate’ AD. Patients from both subgroups were assessed for responses of cognitive and functional abilities, behavioural alterations and changes in global impression to treatment with galantamine 24 mg/day during pivotal clinical studies compared with respective placebo subgroups (n = 257 and n = 61, respectively). Results: After 5-6 months of treatment with galantamine 24 mgday, patients with ‘advanced moderate’ AD showed significantly improved cognitive abilities compared with placebo in the joint data-set pooled from pivotal clinical trials @ < 0.001). In the subgroup of patients with baseline ADAS-cog > 30, patients improved by 2.8 points on the ADAS-cog, compared with a 3.6point decline with placebo (treatment difference, p < 0.001). Approximately half (46%) of these patients improved by 24 points on the ADAS-cog with galantamine compared with 16% with placebo @ < O.OOl), and the mean improvement in the upper quartile (top 25%) of ADAS-cog changes from baseline was 10.6 points compared with 4.8 points in placebo-treated patients. A further 25% showed improvements of 5.1 points compared with a decline of approximately 1.9 points with placebo. In patients who joined the studies with baseline MMSE < 12, ADAS-cog scores improved by 0.9 points in galantamine-treated patients compared with a 5.8-point decline in patients who received placebo (treatment difference, p < 0.001); 26.8% of these galantamine-treated patients improved by 24 points on ADAS-cog compared with